PROJECT SUMMARY Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disorder. Although multiple immune and inflammatory pathways are known to be involved in the development of RA it remains unclear what the triggering mechanisms are. Discovery of any potential causal contributors, including other diseases, like Autism Spectrum Disorder (ASD), is crucially important for disease prevention and developing of new efficient treatments. Moreover, offspring of mothers with RA are at increased risk of perinatal complications and recent reports suggests an increased risk of ASD. ASD is a severe non-curable neuro-developmental disorder. A link to RA and treatment for RA, e.g. medication, may suggest an immune-mediated origin of ASD as a new etiological avenue and a step towards prevention. The goal of this project is to examine the etiological association between RA and ASD; Disentangle and estimate genetic and environmental inherited risk from parents with RA to offspring ASD and examine the risk for RA in individuals with ASD and how these associations are modified by shared risk factors and RA sub- types, sero-negative and sero-positive RA, and timing of the RA exposure. To achieve this goal we will create a prospective cohort of all children born in Sweden between 1997 and 2015, enriched with data from two Swedish genetic data sources, and follow them up to end of 2018 for clinical diagnosis of RA and ASD and apply methods for survival analysis. In Aim 1 we will calculate relative risk of ASD for mothers and fathers with RA compared to the general population, by RA subtype, by sex and by timing of exposure. In Aim 2 we will extend the analyses to study the risk of RA in individuals with ASD. Aim 3 will examine the evidence for shared genetic risk between RA and ASD and study specific genetic markers. We will perform an independent replication of the analyses of Aim 1 and Aim 2 in a similar dataset from Israel.